Pharmaceutical product



Patented Nov. 20, 1928.

UNITED STATES PATENT OFFICE.

WILLIAM JACKSON POPE, OF CAMBRIDGE, ENGLAND, ASSIGNOR TO THE BRITISHDRUG HOUSES LIMITED, 01'' LONDON, ENGLAND, A. BRITISH COMPANY.

vPHARIINIIACEU'I'IGAL PRODUCT.

No Drawing. Original application iiled March 18, 1926, Serial No.95,785, 1925. Divided and this application filed December 7, 1926,Serial No.

used or known to be useful for the purpose. bo

Salts .of naturally occurring alkaloids, as for example cocaine, and ofcertain organic basic substances, which are prepared artificially, asfor example ethocaine (di-ethyll amino-ethyl-para-amino-benzoate) are inextensive use as anaesthetics. The acids in general chosen for thepreparation of these salts are such as yield easily soluble andwell-characterized salts. I

It has been discovered that the borates of such natural or syntheticanaesthetic bases ex ert a far greater anaaesthetic effect when appliedin solution to a sensitive surface, such as that of the eye, nose,throat or ureter, 2 than do solutions of the salts commonly used.

The chemical composition of these borates is such that one molecularproportion of the alkaloid or base is associated with five atomicproportions of boron, in the form of a complex boric acid, and incertain cases, especially if acetone is usedin their preparation,

solvent of crystallization may be included in theircomposition.

My invention relates to those borates of 3 natural or synthetic basesexercising anaesthetic effect which are the products of my invention andare hereinafter defined and inthetic bases.

These boratesare made by double decomposition of the sulphate of thebase with a barium salt of'boric acid.

By this method the sulphate of the base is mixed with an excess ofabarium borate to 40 remove the sulphuric acid from the sulphate of thebase. The barium sulphate is filtered and thoroughly washed withalcohol. The

. clear filtrate is evaporated to a very low volume or to dryness andthen thoroughl cluded in the expression, borates of antes-- vent, togive the desired borate.

The invention is illustrated by thefollowand in Great Britain July 28,153,211. Renewed September ing examples, but the invention is notlimited thereto. The parts are by weight.

Example J.Amydricaine (tetramethyldiaminodimethyl. ethyl carbinylbenzoate) rate.

One part of amydricaine (tetramethyldiaminodimethyl ethyl carbinylbenzoate) base, of which the structural formula is:

(Guam-0H, o- CO'CIHS (CHahN-CH: CHPCHI is dissolved in N-sulphurio acid(3.2 parts approximately) and this solution is added to an aqueoussuspension of a barium borate prepared by mixing 1.05 parts ofcrystalline NEiOCO-O-OIh-CHNMMO:

is dissolved in N-sulphuric acid (5 parts approximately), and thissolution is added to an aqueous suspension of a barium borate preparedby mixing 1.57 parts by weight of crystal-line bariunfhydroxide with1.24 parts by weight of boric acid. After warming for a short time theinsoluble material is filtered and washed with warni alcohol. Thefiltrate and washings are mixed and evaporated, and

y the residue is washed with acetone, filtered, washed with acetone, orother suitable solwashed with more acetone, and dried. The

P value of this material is also about 8.2 1

when tested in the manner described above.

' aoeton Ea: ki-Benzamine benzo vin 1dizlfiamine borate. yl y 2.47 parts:of

structural formula is: r

' n o-oo-odn immev sn I I are dissolved in'N-sult plhuric acid (10 partsapproximately), and is solution is added to an aqueoussuspension of abarium borate prepared by mixing 3.15 parts of crystalline bariumhydroxide with 2.48 parts of boric acid. After warming fora short time'the insoluble material is separated and washed with warm alcohol. Thefiltrate and washings are mixed and evaporated and the residue is washedwith acetone, the solid separated and washed with more acetone. The Pvalue of the material so obtained is also about 8.2 when tested in themanner described above, again u phenol red as an indicator. Example 4. u(dibutylaminopropyl para-aminobenzoate borate.

The pre aration of this substance is carried out in a similar way,except that an equivalent of butynbase, of which the structural formulais:

NarOco o-cm-cm-cm-moma is used in place of. the other basementioned: TheP value of this salt is about 7 .6 when freshli diluted with about 50volumes of ordinary stilled water and using phenol red solution asindicator, the same method of testing being adopted as in the previousexamples. In a similar manner, one may From cocaine (benzo 1 methy ofwhich the structural ormula is our-0 on'oo-oom l lL-OH: nose-canprepare: ecgonine) ethyl carbiny benzoate) borate havin a value of about8.0, using phenol red so ution.

j .1 which the as indicator, under the conditions described for thepreviously mentioned borates; From glycocaine base, of which thestructural formula is omo-oo-O-nncocat-mompara-amino-ortho-hydroxy-benzoate) borate, havin a P value of about 7.6,using phenol dilution as before, and observing similar conditions;

From benzocaine base, of which the structural formula is si -00.00 in.

benzocaine (ethyl .para-amino-benzoate) borate, havin a P value of about6.1 using bromothymol lue solution as indicator;

From phenocaine base, of which the structural formula is ICHPC/N NH O-Cfllr phenocaine di-para-phenetglethenylamidine) borate, aving a P vausing henol red as indicator.

Having thus described the nature of the said invention and the bestmeans I know of carrying the same into practical efiect, I claim 1. Aprocess for the manufacture of borates of anaesthetic bases whichconsists inbringing-together in a liquid .an anaesthetic base in the ormof sulphate and boric acid in the form of. a barium compound.

[2. A process for the manufacture of borates of anaesthetic bases whichconsists-i'n bringing together an aqueous solution of an a borate ofbarium.

3. A process for the m amino-benzoate) which consists in brin ingtogether in a liquid ethocaine- (di-et ylamino-ethylara-amino-benzoate)in the form of sulp ate and boric acid in the form of a barium compound.

4. A process for the manufacture of aborate of ethocaine(di-ethyl-amino-ethyl-para amino-benzoate) which consists in bring ng tother an aqueous solution of ethocaine (dfiethyl-amino-ethyl-para-amino-benzoate) sulphate and a suspension of.aborate a: barium.

In testimony whereof I have signed. my

name to this specification. WILLIAM JACKSON POPE.

glycocaine (methyl diethylamino-acetylred so utionas indicator, andusing the same ue of about 7 .3, a

anaesthetic base sulphate and a suspension of nufacture of aborate ofethooaine (di-ethy -amino-ethyl-para-

